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Cabozantinib (XL184, BMS-907351)
VEGFR2/Met/Ret/Kit/FLT//AXL inhibitor

Cabozantinib (XL184, BMS-907351)

Catalog No. A2977
Size Price Stock Qty
10mM (in 1mL DMSO) $75.00 In stock
Evaluation Sample $28.00 In stock
5mg $70.00 In stock
25mg $200.00 In stock
100mg $680.00 In stock

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Sample solution is provided at 25 µL, 10mM.

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Chemical structure

Cabozantinib (XL184, BMS-907351)

Related Biological Data

Cabozantinib (XL184, BMS-907351)

Related Biological Data

Cabozantinib (XL184, BMS-907351)

Biological Activity

Description Cabozantinib (XL184, BMS-907351) is a potent inhibitor of VEGFR2 with IC50 of 0.035 nM and also inhibits c-Met, Ret, Kit, Flt-1/3/4, Tie2, and AXL with IC50 of 1.3 nM, 4 nM, 4.6 nM, 12 nM/11.3 nM/6 nM, 14.3 nM and 7 nM, respectively.
Targets VEGFR2 c-Met Ret c-Kit Flt-1/3/4 Tie2
IC50 0.035 nM 1.3 nM 4 nM 4.6 nM 12 nM/11.3 nM/6 nM 14.3 nM

Protocol

Cell experiment: [1]

Cell lines

Human microvascular endothelial (HMVEC) cells

Preparation method

The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37 °C for 10 minutes and/or shake it in the ultrasonic bath for a while.Stock solution can be stored below -20°C for several months.

Reaction Conditions

IC50: 6.7 nM, 7 days

Applications

HMVEC cells were incubated with VEGF in the presence of cabozantinib and tubule formation visualized by immunostaining for CD31. Cabozantinib inhibited tubule formation with an IC50 value of 6.7 nM with no evidence of cytotoxicity, showing that cabozantinib exerts an antiangiogenic rather than cytotoxic effect.

Animal experiment: [1]

Animal models

Female nu/nu mice implanted with H441 cells

Dosage form

Oral administration, 100 mg/kg, 8 hours

Applications

A single 100 mg/kg oral dose of cabozantinib resulted in inhibition of phosphorylation of MET 2 to 8 hours postdose in H441 tumors that harbor constitutively phosphorylated MET. This effect was reversible, as MET phosphorylation returned to basal levels by 48 hours after treatment.

Other notes

Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal.

References:

[1] Yakes F M, Chen J, Tan J, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Molecular cancer therapeutics, 2011, 10(12): 2298-2308.

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Chemical Properties

Cas No. 849217-68-1 SDF Download SDF
Chemical Name 1-N-[4-(6,7-dimethoxyquinolin-4-yl)oxyphenyl]-1-N'-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide
Canonical SMILES COC1=CC2=C(C=CN=C2C=C1OC)OC3=CC=C(C=C3)NC(=O)C4(CC4)C(=O)NC5=CC=C(C=C5)F
Formula C28H24FN3O5 M.Wt 501.51
Solubility >25.1mg/mL in DMSO Storage Store at -20°C
General tips No
Shipping Condition No

Research Update

1. Multi-targeted tyrosine kinase inhibitors in clinical development: focus on XL-184 (cabozantinib). Drugs Today (Barc). 2011 Nov;47(11):857-68. doi: 10.1358/dot.2011.47.11.1688487.
Abstract
XL-184 is an inhibitor of multiple receptor tyrosine kinases, particularly Met, VEGFR-2 and Ret, with clinical activities against tumors of both epithelial and mesenchymal origins, particularly medullary thyroid cancer and cancers metastatic to the bone.
3. Cabozantinib inhibits prostate cancer growth and prevents tumor-induced bone lesions. Clin Cancer Res. 2014 Feb 1;20(3):617-30. doi: 10.1158/1078-0432.CCR-13-0839. Epub 2013 Oct 4.
Abstract
XL-184, a multi-tyrosine kinase inhibitor targeting MET and VEGFR2, induces resolution of bone scan lesions in men with castration-resistant prostate cancer bone metastases possibly through a direct antitumor activity, modulating bone, or both.
4. A dose-ranging study of cabozantinib in men with castration-resistant prostate cancer and bone metastases. Clin Cancer Res. 2013 Jun 1;19(11):3088-94. doi: 10.1158/1078-0432.CCR-13-0319. Epub 2013 Apr 3.
Abstract
The efficacy and tolerability of XL-184, a MET/VEGFR2 inhibitor improving bone scans in mCRPC patients, at lower starting doses were determined due to XL-184 induced AE.
5. In Vitro and In Vivo Activity of Cabozantinib (XL184), an Inhibitor of RET, MET, and VEGFR2, in a Model of Medullary Thyroid Cancer. Thyroid. 2013 Dec;23(12):1569-77. doi: 10.1089/thy.2013.0137. Epub 2013 Sep 17.
Abstract
XL-184, a multi-tyrosine kinase inhibitor targeting RET, MET and VEGFR2, inhibited activated RET mutations associated with MTC and effectively suppressed the growth of MTC tumor cell models both in vivo and in vitro.

Background

Cabozantinib (also called XL184, BMS-907351 Cometriq [1]), is an inhibitor of multiple receptor tyrosine kinases (RTKs), including vascular endothelial growth factor receptor 2 (VEGFR2), hepatocyte growth factor receptor (MET), and rearranged during transfection (RET) [2] [3], with IC50 values of 0.035 nmol/L, 1.3 nmol/L and 5.2 nmol/L to VEGFR2, MET and RET, respectively [4].

RTKs transmit a wide array of extracellular signals for regulating differentiation and proliferation to cells. Ligand binding triggers many events such as autophosphorylation of tyrosine residues and receptor dimerization [5].

TT cell line was a human MTC cell line that had an activating C634W RET mutant and was expressing calcitonin. In this cell line, cabozantinib inhibited the autophosphorylation of RET with an IC50 value of 85 nmol/L. In TT cells grown for 72 h in 10% serum, cabozantinib dose-dependently inhibited cell proliferation with an IC50 value of 94 nmol/L [4].

Administrated with cabozantinib daily orally at doses of 10, 30, or 60 mg/kg, nu/nu mice bearing TT xenograft tumors, showed a significantly inhibited tumor growth compared with vehicle-treated group. At both doses of 30 and 60 mg/kg, cabozantinib caused markedly and significantly reduced circulating calcitonin (75%; p< 0.005) in serum compared with vehicle-treated control animals [4].

References:
[1].  Michael G. Doran, Daniel E. Spratt, John Wongvipat, et al. Cabozantinib Resolves Bone Scans in Tumor-Naїve Mice Harboring Skeletal Injuries. Molecular Imaging, 2014, 13:1-5.
[2].  Rossella Elisei, Martin J. Schlumberger, Stefan P. Müller, et al. Cabozantinib in Progressive Medullary Thyroid Cancer. J. Clin. Oncol., 2013, 31(29):3639-46.
[3].  Razelle Kurzrock, Steven I. Sherman, Douglas W. Ball, et al. Activity of XL184 (Cabozantinib), an Oral Tyrosine Kinase Inhibitor, in Patients with Medullary Thyroid Cancer. J. Clin. Oncol., 2011, 29(19):2660-6.
[4].  Frauke Bentzien, Marcus Zuzow, Nathan Heald, et al. In Vitro and In Vivo Activity of Cabozantinib (XL184), an Inhibitor of RET, MET, and VEGFR2, in a Model of Medullary Thyroid Cancer. Thyroid, 2013, 23(12):1569-1577.
[5].  Xianhua Piao, Robert Paulson, Peter van der Geer, et al. Oncogenic mutation in the Kit receptor tyrosine kinase alters substrate specificity and induces degradation of the protein tyrosine phosphatase SHP-1. Proc. Natl. Acad. Sci. USA., 1996, 93(25):14665-14669.